The US Food and Drug Administration (FDA) has approved zilurgisertib (Atebrioz) tablets to reduce the volume of total new heterotopic ossification (HO) in adults and pediatric patients aged 12 years and older with fibrodysplasia ossificans progressiva (FOP).1
Key Takeaways
- The FDA approved zilurgisertib (Atebrioz), an oral ALK2 inhibitor, for FOP in patients aged 12 years and older, making it the third approved FOP therapy.
- In PROGRESS, total new HO volume fell by a mean of 3.2 cm³ with zilurgisertib vs a 24.6 cm³ increase with placebo at week 24.
- The prespecified primary endpoint, proportion of patients with new HO lesions, showed an 81% relative reduction but did not reach statistical significance (P = .0986).
- No AEs led to discontinuation or dose reduction; the label warns of embryo-fetal toxicity.
- Pediatric cohorts down to age 2 years are ongoing.
The approval, announced September 25, 2026, is based on the randomized, double-blind, placebo-controlled phase 2 PROGRESS trial. The recommended starting dosage is 100 mg orally once daily, with or without food.1
Zilurgisertib, an oral small-molecule activin receptor-like kinase 2 (ALK2) inhibitor developed by Mirum Pharmaceuticals under license from Incyte, is the third FDA-approved therapy for FOP. It follows the 2023 approval of palovarotene (Sohonos), an oral retinoic acid receptor gamma agonist, and the August 2026 approval of garetosmab-grts (Pasatru), an intravenous activin A antibody dosed every 4 weeks. Unlike garetosmab, whose label is limited to adults, zilurgisertib is indicated for patients as young as 12 years.1,2,3,4
Cohort 1 of PROGRESS randomized 63 patients aged 12 years and older 1:1 to zilurgisertib 100 mg (n = 32) or placebo (n = 31) once daily for 24 weeks. A single-arm, open-label extension followed, during which all patients received zilurgisertib 100 mg daily. Mean age at baseline was approximately 21 years, and treatment groups were generally balanced, according to Mirum and Incyte.1,2
The FDA based its efficacy assessment on change from baseline in the volume of total new HO vs placebo during the double-blind period, measured by whole-body CT. At week 24, patients receiving zilurgisertib had a mean decrease of 3.2 cm3, compared with a mean increase of 24.6 cm3 in the placebo group (nominal P = .004).1,2
The prespecified primary endpoint of PROGRESS was the proportion of patients developing new HO lesions at week 24. One patient (3.1%) in the zilurgisertib arm developed new lesions vs five patients (16.7%) in the placebo arm, an 81% relative reduction (P = .0986). This difference did not reach statistical significance.2
Zilurgisertib secondary outcomes and safety in FOP
Mean volume of new HO lesions at week 24 was 0.003 cm3 with zilurgisertib vs 6.57 cm3 with placebo, a reduction exceeding 99% (nominal P < .0001). Annualized new flares averaged 2.34 with zilurgisertib vs 4.55 with placebo.2
Through week 48, no new HO lesions were observed among 61 patients with available whole-body CT data, including patients crossing over from placebo at week 24. From week 24 to week 48, total HO lesion volume continued to decline in the continuous zilurgisertib group (mean change, −6.37 cm3) and the crossover group (mean change, −5.32 cm3).2
According to Mirum and Incyte, most adverse events (AEs) during the placebo-controlled period were mild or moderate, and no AEs led to discontinuation or dose reduction. The most common AEs with zilurgisertib were FOP flare-up or FOP-related pain (25%), headache (21.9%), upper respiratory tract infection (21.9%), arthralgia (18.8%), epistaxis (12.5%), and nausea (12.5%). Serious AEs and grade 3 or higher AEs occurred at low rates in both arms.2
The label carries a warning for embryo-fetal toxicity based on animal data. Patients of reproductive potential should use effective contraception and discontinue zilurgisertib immediately if pregnancy occurs. The label also restricts coadministration with certain concomitant medications.1
Joanne Quan, MD, chief medical officer at Mirum Pharmaceuticals, said at the time of the PROGRESS data release, "People living with FOP and their families urgently need additional treatment options."² The pivotal Cohort 1 results were presented as a late-breaking abstract at ENDO 2026 in June.²
Additional PROGRESS cohorts are evaluating zilurgisertib in children aged 6 to younger than 12 years and in children aged 2 to younger than 12 years. The FDA granted the application fast track, priority review, and orphan drug designations.1,2
References
